title: Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA).
abstract: BACKGROUND
  The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA).
  
  
  METHODS
  Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed.
  
  
  RESULTS
  Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs.
  
  
  CONCLUSIONS
  The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA.
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
authors.forename: Nikola
authors.initials: N
authors.lastname: Lepse
authors.forename: Coen A
authors.initials: CA
authors.lastname: Stegeman
authors.forename: Minke G
authors.initials: MG
authors.lastname: Huitema
authors.forename: Berber
authors.initials: B
authors.lastname: Doornbos-van der Meer
authors.forename: Henko
authors.initials: H
authors.lastname: Tadema
authors.forename: Abraham
authors.initials: A
authors.lastname: Rutgers
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Limburg
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
mesh_terms: D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D002469:Cell Separation; D002648:Child; D015267:Churg-Strauss Syndrome / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D007378:Interleukins / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D055953:Microscopic Polyangiitis / Q000097:blood / Q000276:immunology*; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001324:Autoantigens; D007378:Interleukins; D000098546:Interleukin-21